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Biomedical subjects

I K Ho

Publications and source records attributed to I K Ho.

At least 109 records · Page 6Linked to original sources
PubMed1994

Changes in the central dopaminergic systems in the streptozotocin-induced diabetic rats.

The behavioral response, dopamine metabolism, and characteristics of dopamine subtypes after developing the hyperglycemia were studied in the striata of rats. In animals developed hyperglycemia, the on-set and duration of cataleptic behavior responded to SCH 23390 injection was delayed and shortened, respectively. However, the cataleptic responses to spiperone occurred significantly earlier in on-set and prolonged in duration. Dopamine metabolites, dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), were significantly reduced in the striata of hyperglycemic rats. However, level of DA was significantly increased. It is noted that the ratios of DOPAC and HVA to DA were decreased, suggesting decreased turnover of DA. The affinity of striatal D-1 receptors was significantly increased without changes in the number of binding sites, while the maximum binding number of D-2 receptors was significantly increased without affecting its affinity in the diabetic rats. These results indicate that the dopaminergic activity in the striata was altered in hyperglycemic rats. Furthermore, it suggests that the upregulation of dopamine receptors might be due to the decreased dopamine metabolism.

Animals↗
PubMed1994

Naloxone-precipitated morphine withdrawal increases pontine glutamate levels in the rat.

Extracellular fluid (ECF) levels of glutamate (Glu) and aspartate (Asp) were measured in the locus coeruleus (LC) during morphine withdrawal by using microdialysis in conscious morphine-dependent Sprague-Dawley rats. Guide cannulae were implanted chronically and rats were given intracerebroventricular (i.c.v.) infusions of morphine (26 nmol/1 microliters/hr) or saline (1 microliters/hr) for 3 days. Microdialysis probes (2 mm tip) were inserted into the LC 24 hr before precipitation of withdrawal by i.c.v. injection of naloxone (12 or 48 nmol/5 microliters). Behavioral evidence of withdrawal (teeth-chattering, wet-dog shakes, etc.) was detected following naloxone challenge in morphine, but not in saline-infused rats. Increases (P < 0.01) in ECF levels of Glu (and Asp, to a lesser degree) were noted after naloxone-precipitated withdrawal only in the morphine group. The ECF Glu levels in the LC increased from 9.6 +/- 2.7 to 15.5 +/- 5.0 microM following 12 nmol/5 microliters naloxone, and from 9.5 +/- 1.9 to 20.5 +/- 3.3 microM following 48 nmol/5 microliters naloxone, before and in the first 15 min sample after the precipitation of withdrawal in the morphine-dependent rats, respectively. These results provide direct evidence to support the role of excitatory amino acids within the LC in morphine withdrawal.

Animals↗
PubMed1994

Tolerance development to butorphanol: comparison with morphine.

In order to evaluate and to compare the time course, dose response, and the degree of tolerance development to butorphanol and morphine, rats were continuously intracerebroventricularly (ICV) infused with saline vehicle (1 microliter/h), butorphanol (6.5, 13, 26, and 52 nmol/microliters/h), or morphine (1.6, 6.5, and 26 nmol/microliters/h) through osmotic minipumps for 1 to 3 days. The tail-flick responses were determined pre-, during, and postinfusion. Tolerance to morphine developed faster than that to butorphanol. The antinociceptive response to the ICV challenge dose (6 h after the termination of drug infusion) of butorphanol or morphine was decreased significantly and there was a negative correlation between the dose of the drug infused and the observed antinociceptive response. In terms of butorphanol and morphine tolerance, a parallel rightward shift in the dose-response curve was produced with the degree of shift proportional to the log of the infusion dose. In tail-flick tests, the shifts of the dose-response curves for butorphanol and morphine in tolerant animals were 11.8- and 46.3-fold, respectively. However, in the acetic acid writhing test, the shifts of the dose-response curves for butorphanol and morphine in tolerant animals were 11.3- and 11.7-fold, respectively. These results suggest that there is a greater degree of tolerance to morphine than there is to butorphanol, but the degree of butorphanol tolerance is still substantial. In addition, two pain assays (tail flick vs. writhing) yielded different estimations of tolerance in a comparison of morphine and butorphanol.

Animals↗
PubMed1994

Crosstolerance between butorphanol and morphine in rats.

To investigate the antinociceptive effects of morphine and U-50,488 after continuous administration with butorphanol, rats were intracerebroventricularly (ICV) infused with butorphanol (26 nmol/microliters/h) through osmotic minipumps for 3 days. Six hours after termination of infusion, the rats were challenged with different doses of morphine or U-50,488. Antinociceptive effects, as assessed by tail-flick and acetic acid writing tests, were measured 15 min after challenge. Development of crosstolerance to morphine was evident in butorphanol-infused animals. The study also revealed that crosstolerance to butorphanol developed in continuously ICV morphine-infused animals. Continuous ICV infusion with butorphanol produced a marked rightward shift of the antinociceptive dose-response curve resulting from U-50,488 challenge. These results showed that there is an antinociceptive crosstolerance between butorphanol and morphine, and crosstolerance to U-50,488 developed in continuously butorphanol-infused animals. The present data suggested that chronic ICV treatment with high doses of butorphanol can lead to desensitization of the antinociceptive systems mediated through the central kappa as well as mu receptors in rats.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1994

Interactions of ginsenosides with ligand-bindings of GABA(A) and GABA(B) receptors.

1. Total saponin fraction decreased the affinity of specific [3H]muscimol binding without changes in Bmax. Ginsenoside Rb1 Rb2, Rc, Re, Rf and Rg1 inhibited the specific [3H]muscimol binding to the high-affinity site. 2. Total saponin fraction increased the affinity of specific [3H]flunitrazepam binding. Ginsenoside Re and Rf enhanced specific [3H]flunitrazepam binding. 3. Total saponin fraction decreased the affinity of specific [35S]TBPS binding without changes in Bmax. Ginsenosides did not affect specific or non-specific [35S]TBPS binding. 4. Total saponin fraction decreased the affinity of specific [3H]baclofen binding without changes in Bmax. Ginsenoside Rc inhibited specific [3H]baclofen binding.

Animals↗
PubMed1994

Studies on picrotoxin binding sites of GABAA receptors in rat cortical synaptoneurosomes.

Experiments were performed to characterize [35S]TBPS binding in rat cortical synaptoneurosomes, which have vesicular structures containing both pre- and postsynaptic elements. Scatchard analysis revealed a single component of [35S]TBPS binding sites with KD and Bmax values of 76.1 nM and 1.97 pmoles/mg protein, respectively, under physiological conditions. GABA and muscimol inhibited [35S]TBPS binding in a concentration-dependent manner. IC50 values of these GABAA agonists in displacing synaptoneurosomal [35S]TBPS binding are comparable to previously reported EC50 values of the agonist-stimulated 36Cl- uptake in synaptoneurosomes by these agents. Furthermore, the IC50 values of these GABAA agonists were better correspondence to those determined by [3H]muscimol binding in synaptoneurosomal preparations as reported by Delorey and Brown (3) than those determined in membrane preparations. Although bicuculline increased [35S]TBPS binding in a concentration dependent manner in cortical membranes, it did not affect synaptoneurosomal [35S]TBPS binding. Benzodiazepine agonists and inverse agonists (0.1 to 10 microM) did not show any effects on the binding in the absence of muscimol. However, benzodiazepine agonists potentiated and inverse agonists antagonized muscimol-induced inhibition of synaptoneurosomal [35S]TBPS binding. In addition, an anesthetic steroid, THDOC, and pentobarbital inhibited synaptoneurosomal [35S]TBPS binding in a concentration dependent manner. These results suggest that allosteric modulation of [35S]TBPS binding by various ligands which interact with GABAA supramolecular complexes remain intact in synaptoneurosomes. It appears that this preparation is useful for investigating correlation between functional 36Cl- uptake and individual binding studies of each of the GABAA receptor complex.

Animals↗
PubMed1994

In situ hybridization evidence of differential modulation by pentobarbital of GABAA receptor alpha 1- and beta 3-subunit mRNAs.

Tolerance to and withdrawal from pentobarbital were induced in rats by continuous intracerebroventricular infusion via subcutaneously implanted osmotic minipumps. In situ hybridization of GABAA receptor alpha 1- and beta 3-subunit mRNA was conducted using synthetic 3'-end 35S-dATP-labeled oligodeoxynucleotide probes. Results were quantified by film densitometry. In animals that were tolerant to pentobarbital, levels of alpha 1-subunit mRNA were decreased in hippocampus, superior colliculus, and inferior colliculus, but levels of beta 3-subunit mRNA were not affected. Dramatically increased levels of GABAA receptor subunit mRNA were observed in animals 24 h after withdrawal from chronic pentobarbital treatment. These increases occurred in cerebral cortex and cerebellum for the alpha 1 subunit and in cerebral cortex only for the beta 3-subunit. These data provide further support to the structural and pharmacological GABAA receptor heterogeneity in discrete brain areas. The observed changes of subunit expression may underlie, at least in part, the receptor up- and down-regulation observed in receptor ligand binding studies.

Animals↗
PubMed1994

The potent depressant effects of N3-phenacyluridine in mice.

The hypnotic activity of N3-phenacyluridine in 2.0 mumol/mouse by intracerebroventricular (i.c.v.) injection was 20 times stronger than that of known N3-benzyluridine. In 0.5 mumol/mouse, i.c.v., this compound strongly potentiated both pentobarbital- and diazepam-induced sleep as compared to N3-substituted uridines, including N3-benzyluridine. Furthermore, the compound caused motor incoordination as well as decreasing spontaneous activity in the same dose. These results indicate that among the N3-substituted uridines and related compounds previously reported, N3-phenacyluridine possesses potent depressant effects.

Animals↗
PubMed1993

Involvement of delta-opioid receptors in physical dependence on butorphanol.

Butorphanol, a synthetic agonist/antagonist, has been shown to act on mu-, delta- and kappa-opioid receptors. However, the relative involvement of opioid receptor subtypes in mediating butorphanol dependence is not known. In the present study, naltrindole, a delta-selective non-peptide antagonist, was administered intracerebroventricularly (i.c.v.) to mask supraspinal delta-opioid receptors before and during the induction of butorphanol dependence. Treatment with naltrindole (0.1, 1, or 10 nmol/5 microliters per rat) significantly blocked naloxone-, a nonspecific antagonist, precipitated butorphanol withdrawal behaviors (escape behavior, teeth-chattering, wet shakes, forepaw tremors, ptosis, diarrhea, body weight loss, and hypothermia) at all doses tested, and decreased ejaculation at 0.1 nmol in butorphanol-infused rats. In contrast, naltrindole treatment had no effect on yawning, nor urination. These results indicate that central delta-opioid receptors are involved in mediating butorphanol dependence in rats.

Animals↗
PubMed1993

Effects of nor-binaltorphimine on butorphanol dependence.

Butorphanol has been shown to act on mu-, delta-, and kappa-opioid receptors. However, the relative involvement of different opioid receptor subtypes in butorphanol dependence is not known. In the present study, nor-binaltorphimine, a long-acting non-peptide kappa-opioid receptor antagonist, was employed to mask central kappa-opioid receptors before and during the induction of butorphanol dependence in rats, so that the involvement of kappa-opioid receptors could be elucidated. The results revealed that treatment with nor-binaltorphimine markedly blocked naloxone-precipitated withdrawal signs of escape behavior, teeth-chattering, wet shakes, ptosis, body weight loss, and hypothermia at all doses tested, and attenuated the withdrawal symptoms of forepaw tremors (24 nmol: P < 0.001) and diarrhea (12 nmol: P < 0.05; 24 nmol: P < 0.01). In contrast, nor-binaltorphimine had no effect on yawning, ejaculation, nor urination in butorphanol-infused rats undergoing withdrawal. Three days of butorphanol infusion significantly increased KD values (in the cortex and striatum), decreased Bmax (in the cortex only) of [3H]U-69,593 binding, and shifted Ki of nor-binaltorphimine against [3H]U-69,593 (4.5 nM) binding in the cortex by more than 10-fold. Treatment with nor-binaltorphimine blocked the effects of butorphanol on kappa-opioid receptors. It is therefore concluded that kappa-opioid receptors are involved in mediating escape behavior, teeth-chattering, wet shakes, forepaw tremors, ptosis, diarrhea, weight loss, and hypothermia in butorphanol-dependent rats undergoing withdrawal. Furthermore, kappa-opioid receptors become desensitized to agonists (in the cortex and striatum), down-regulated (in the cortex), and supersensitive to antagonists in butorphanol-dependent rats.

Animals↗
PubMed1993

Region-specific changes of GABAA receptors by tolerance to and dependence upon pentobarbital.

An experimental model for inducing tolerance to and dependence upon pentobarbital was characterized. Rats were infused with pentobarbital, 300 micrograms/10 microliter per h i.c.v. for 6 or 7 days, through pre-implanted cannulas by osmotic minipumps. Measurement of brain and serum levels showed that pentobarbital remained mainly inside of the brain. Measurements of sleeping time and susceptibility to convulsant-induced seizures indicated a substantial degree of tolerance and dependence (24 h after termination of infusion). Results of GABAA receptor binding assays showed marked regional variations. While [35S]t-butylbicyclophosphorothionate (TBPS) binding sites were increased in frontal cortices and striata of pentobarbital-dependent animals, KD was increased in striata of tolerant animals. Dependence upon pentobarbital was correlated with increased [3H]flunitrazepam binding sites in all three regions examined. Both high and low affinity [3H]muscimol binding sites were increased in dependent animals, but low affinity sites were decreased in frontal cortices of tolerant animals. KDs of [3H]muscimol high affinity sites were increased in cerebellum after animals developed dependence upon pentobarbital. KDs of [3H]muscimol low affinity sites were decreased in striata of pentobarbital tolerant animals. These findings further support the hypothesis that GABAA receptors in discrete areas of the brain have different subunit compositions and are regulated differentially by pharmacological modulators.

Animals↗
PubMed1993

Site and mechanism of behavioral tolerance to cocaine: a study of dopamine release in Wistar-Kyoto and spontaneously hypertensive rats.

Wistar-Kyoto and spontaneously hypertensive rats received i.v. infusions of cocaine hydrochloride (60 mg/kg per day) for 3, 7, and 14 days, or saline for 7 days. Acute cocaine challenge (40 mg/kg, s.c.) was given to treated and control rats 24 hr after the termination of each infusion period. There were no strain differences in brain levels of cocaine during cocaine infusion, nor after cocaine challenges. There were no strain differences in resting levels of [3H]dopamine release. Release of [3H]dopamine decreased in nuclei accumbens of 7- and 14-day cocaine-infused animals. Release of [3H]dopamine was maximal in both brain regions 2 hr after acute cocaine challenge. After 14 days of cocaine infusion, cocaine challenge in both strains reduced [3H]dopamine release in the nucleus accumbens, but not in the striatum; the reduction being greater in Wistar-Kyoto rats. The behavioral tolerance which accompanies similar cocaine infusion regimens may be related to striatal "tolerance" to cocaine-induced dopamine release.

Animals↗
PubMed1993

Differential effects on GABAA receptor gamma 2-subunit messenger RNA by tolerance to and withdrawal from pentobarbital--an in situ hybridization study.

The heterogeneity of the GABAA receptors has been confirmed structurally and functionally. The present study demonstrates the pharmacological heterogeneity of the GABAA receptors. Rats were rendered tolerant to pentobarbital by continuous intracerebroventricular infusion via osmotic minipumps and abruptly withdrawn from pentobarbital. In situ hybridization of mRNA coding for the GABAA receptor gamma 2-subunit showed decreases of mRNA levels in superior and inferior colliculus in pentobarbital tolerant rats compared to rats in withdrawal. In rats 24-hr after withdrawal from pentobarbital, increases of mRNA levels in neocortex, piriform cortex and in granular and Purkinje cell layers of the cerebellum were observed. These results indicate the fast adaptation of GABA synapses in response to abrupt withdrawal from chronic pentobarbital treatment. The differential responsiveness seen in different areas further confirms the pharmacological heterogeneity of the GABAA receptors. The observed increases and decreases of mRNA may underlie, at least in part, the previously reported changes in Bmax of GABAA receptor ligand binding sites.

Animals↗
PubMed1993

Opioid antagonists and butorphanol dependence.

Butorphanol has been known to act on mu-, delta-, and kappa-opioid receptors, mu- and possibly delta-receptors are thought to mediate morphine dependence. Relative to morphine, butorphanol has a higher affinity for mu- and delta-receptors. In the present study, beta-funaltrexamine (beta-FNA) and naltrindole (NTI) (nonequilibrium mu- and delta-antagonist, respectively) were used to precipitate withdrawal in butorphanol-dependent rats. It was found that beta-FNA (12, 24, 48, and 100 nM) did not elicit significant withdrawal behaviors, while NTI caused teeth-chattering (100 nM), wet shakes (100 nM), forepaw tremors (24 nM), yawning (48 and 100 nM), ejaculation (24 nM), and urination (100 nM). The present results indicate that delta-opioid receptors may be involved in mediating butorphanol dependence, while the involvement of mu-opioid receptors needs to be further investigated.

Animals↗
PubMed1993

Preparation and pharmacological evaluation of N3-substituted thymidine derivatives as central depressants.

Central depressant effects in mice of N3-substituted thymidines (Td) (1) were examined by intracerebroventricular (i.c.v.) injection. Nine derivatives including the methyl, ethyl, propyl, allyl, benzyl, xylyl and alpha-phenylethyl derivatives at the N3-position of 1 were synthesized and their pharmacological effects were evaluated by using hypnotic activity, pentobarbital-induced sleep prolongation and locomotor activity as indices for central depressant effects. At a dose of 2.0 mumol/mouse, the values of mean sleeping time induced by N3-benzylthymidine (6), N3-o-xylylthymidine (7), N3-m-xylylthymidine (8), N3-p-xylylthymidine (9) and N3-alpha-phenylethylthymidine (10) were 61, 30, 48, 45 and 23 min, respectively. These derivatives (2.0 mumol/mouse) prolonged pentobarbital-induced (40 mg/kg, i.p.) sleeping time. None of the alkyl (2-4) or allyl (5) derivatives exerted hypnotic activity, although the derivatives tested (2-10) significantly prolonged the pentobarbital-induced sleeping time. Compound 1 and its xylyl derivatives tested (0.25 mumol/mouse, i.c.v.) decreased locomotor activity. These results indicate that thymidine derivatives have central depressant activity, and the benzyl derivatives but not alkyl derivatives possess a hypnotic activity.

Animals↗
PubMed1993

Sedative and hypnotic activities of pyrimidine nucleoside derivatives.

N3-Substituted pyrimidine nucleoside and their related compounds were synthesized. The central nervous system (CNS) depressant effect of the compounds such as hypnotic activity and synergistic effect with pentobarbital have been evaluated. N3-Phenacyl derivatives of uridine (2), thymidine (3), deoxyuridine (4), 6-azauridine (5) and arabinofuranosyluracil (6) exhibited the hypnotic activity, whereas N3-phenacyl-2',3'-O-isopropylideneuridine did not. Compound 2, 3, 4 and 6 significantly enhanced pentobarbital-induced sleep. The results indicate that CNS depressant effect of pyrimidine nucleoside derivatives might relate to functional group at the N3-position on oxopyrimidine ring and stereospecificity of sugar moiety at the N1-position.

Animals↗
PubMed1993

Induction of tolerance to and physical dependence on pentobarbital continuous intracerebroventricular administration.

A new model of barbiturate tolerance and dependence was developed using i.c.v. infusion of pentobarbital. Male Harlan Sprague-Dawley rats weighing 250 to 300 were implanted with i.c.v. cannulae and infused with sodium pentobarbital (500 micrograms/10 microliters/hour) for 6 days. The pentobarbital-infused group had a shorter duration of pentobarbital-induced loss of righting reflex than the saline-infused group. When i.c.v. pentobarbital- and saline-infused rats were injected with sodium pentobarbital (60 mg/kg i.p.), the time course of pentobarbital levels in the serum and in the brain were not significantly different. The infusion of pentobarbital also did not induce hepatic drug-metabolizing enzymes. The depth of thiopental-induced hypothermia was decreased by i.c.v. pentobarbital infusion. During the course of the infusion, the basal body temperature of the pentobarbital-infused rats did not change. Two days after the infusion was discontinued, the basal body temperature was elevated. The increase in body temperature lasted for 8 days. Twenty-four hours after the infusion was discontinued, the pentobarbital-infused rats had a significantly shorter onset of t-butylbicyclophosphorothionate (TBPS)-induced convulsions. These studies show that i.c.v. infusion can be used to induce pentobarbital tolerance and dependence. This model has the advantage that issues related to induction of hepatic drug-metabolizing enzymes are eliminated, and it may be useful in the study of barbiturate addiction.

Animals↗